HIV-1 persists despite prolonged periods of maximally suppressive antiretroviral therapy, and rapidly rebounds once treatment is stopped. The development of clinical strategies that reduce HIV-1 persistence and may lead to a long-term drug-free remission of HIV-1 infection represents one of the highest priorities in current HIV-1 research. Such clinical interventions require a detailed knowledge of the cell populations that serve as a long- term reservoir for HIV-1, and can be specifically targeted to reduce viral persistence. Here, we hypothesize that HIV-1 can persist life-long by infecting CD4 T cell populations with stem cell-like properties that can self-renew through homeostatic proliferation and simultaneously repopulate differentiated effector T cell populations. Recent work demonstrates that IL-17-secreting CD4 T cells (Th17) are guided by stem-cell like transcriptional signatures, have extremely long in vivo half-lives and can serve as precursor cell populations for differentiated effector CD4 T cells. In this way, Th17 cells are remarkably similar to T memory stem cells (Tscm), a recently- discovered cell population with a multipotent developmental program that can repopulate all CD4 memory cell subsets, while being maintained by homeostatic self-renewal. To determine whether Th17 and Tscm can serve as a reservoir for viral long-term persistence, we will quantify the amount of HIV-1 DNA and replication- competent virus in these cells, and longitudinally compare viral sequences from these cells to more differentiated T cell subsets and plasma sequences. As a possible strategy to target stem cell-like T cells, we propose to focus on pharmaceutical agents that manipulate wnt/beta-catenin, a phylogenetically-conserved stem cell-specific signaling pathway that maintains the quiescence and multipotency of stem cell-like T cells, and in this way may contribute to long-term HIV-1 persistence. Pharmaceutical targeting of the beta-catenin pathway is currently explored in clinical studies to eliminate cancer stem cells, a small group of long-lived, self- renewing cells with strong oncogenic potential that persist despite classical antineoplastic therapy and in that sense may resemble latently HIV-1 infected stem cell-like T cells that persist despite HAART. Using an existing small molecule inhibitor of the wnt/beta-catenin signaling pathway with an excellent safety/tolerability profile that is currently in phase I clinical trials or eradicating cancer stem cells, we will test whether pharmaceutical targeting of wnt/beta-catenin can be used to induce differentiation of HIV-1 infected T cells with stem cell-like properties and to limit HIV-1 persistence. By defining stem cell-like qualities of immune memory that support HIV-1 persistence, and evaluating possible interventional options to target these, the proposed studies may critically advance the quest for inducing long-term drug-free remissions of HIV-1 infection and lead to translational clinical studies evaluating wnt/beta-catenin inhibitors for reducing HIV-1 persistence in vivo.